(1) Field of the Invention
This invention relates to novel quinoxaline derivatives and salts thereof, which exhibit phosphodiesterase type 9 (PDE9)-inhibiting activity and are useful as treating agent of dysuria and the like.
(2) Description of Related Art
Dysuria can be largely divided into emptying disorder due to inability to urinate with sufficient force at the time of emptying the bladder, and bladder-filling disorder due to inability to retain urine during the filling time. Presently, α1 blocker is frequently used for treating the emptying disorder and anticholine agent, for treating bladder-filling disorder. These drugs, however, have such defects as insufficient long-term therapeutic effect or reduction in quality of life (QOL) induced by side effect, and development of drugs having new activity mechanism different from the conventional approach, for example, drugs utilizing potassium channel opening activity, cyclic guanosine-3′,5′-monophosphate (cGMP) degradation inhibiting activity, is in demand.
cGMP plays an important role in variegated cellular events such as smooth muscle relaxation, memory and learning function control, photoreaction of retina, cell proliferation, immunoreaction and the like. In normal cells, cGMP synthesis by nitrogen monoxide-(NO)-cGMP system and cGMP degradation by PDE system are maintained at balanced levels. Whereas, within the cells under various states of disorder, function of the NO-cGMP system lowers to render the cGMP synthesis level in the cells low, while the cGMP degradation level is unchanged. Hence, cGMP concentration in the affected cells becomes low. It is expected, therefore, prevention of cGMP degradation in the cells to redress the reduction in intracellular cGMP concentration would be useful for treating or preventing the diseases.
While there are many types of PDE, those which specifically hydrolyze cGMP are type 5 (PDE5), type 6 (PDE6) and type 9 (PDE9). Of these, PDE9 shows the least Km value (J. Biol. Chemistry, Vol. 273, No. 25, 15559-15564 (1998)), has high affinity to cGMP and is considered to participate in degradation of cGMP with particular significance.
Pyrazolopyrimidine derivatives as the compounds exhibiting PDE9-inhibiting activity are disclosed in PCT International Publications WO 03/037432 Pamphlet, WO 03/037899 Pamphlet and WO 2004/018474 Pamphlet, and it has been reported as to the derivatives, for example, that they are useful for treating insulin-resistant diseases or the circulatory system disorder, and for improving perception, learning and memory functions.
However, there exists no literature discussing relevancy of PDE9-inhibiting action to therapeutic efficacy on uropathy.
On the other hand, J. Med. Chem., 34, 2671-2677 (1991) discloses quinoxaline derivatives having PDE1-inhibiting activity and PDE4-inhibiting activity. However, this reference contains no description or suggestion that the derivatives have PDE9-inhibiting activity, or that PDE9-inhibiting activity is useful for treating dysuria or the like.